Pharmacokinetics: Absorption and Distribution

Membrane Transport & Absorption - Getting In!

• Cell Membrane: Phospholipid bilayer, proteins; fluid mosaic model.
• Passive Transport Mechanisms:
  • Simple Diffusion:
    • Major route.
    • Down conc. gradient; no energy.
    • Favors lipid-soluble, unionized drugs.
    • Fick's Law: Rate $\propto \frac{\text{Surface Area} \times (\text{C}_1-\text{C}_2) \times \text{Permeability}}{\text{Thickness}}$
    • pH & Ionization: Henderson-Hasselbalch eq. for ionization.
      • Acids: $pH - pKa = \log([\text{Ionized A}^-]/[\text{Unionized HA}])$
      • Bases: $pKa - pH = \log([\text{Ionized BH}^+]/[\text{Unionized B}])$
    • 📌 Unionized form is lipid-soluble & absorbed.
      • Acidic drugs (Aspirin): ↑ unionized in acidic pH (stomach).
      • Basic drugs (Morphine): ↑ unionized in alkaline pH (intestine).
  • Filtration: Small water-soluble drugs (< 100-200 Da) via aqueous pores.
• Carrier-Mediated Transport: Uses transporters; specific, saturable, competitive.
  • Facilitated Diffusion: Down gradient, no energy (e.g., GLUT for glucose).
  • Active Transport: Against gradient, needs ATP (e.g., Na+/K+ ATPase, SGLT1).
    • Efflux: P-glycoprotein (MDR1) pumps out drugs, ↓ absorption.
• Vesicular Transport (Endo/Exocytosis): Large molecules (e.g., Vit B12-IF).

⭐ P-glycoprotein (MDR1), an efflux pump, significantly impacts drug absorption and bioavailability, contributing to multidrug resistance.

Routes & Bioavailability - The Entry Game

• Routes of Administration:
  • Enteral: Oral (PO), Sublingual (SL), Rectal (PR).
    • PO: Common, convenient; subject to first-pass.
    • SL/Buccal: Bypasses first-pass (Nitroglycerin); rapid.
    • Rectal: Partial (≈50%) first-pass bypass; useful if N/V.
  • Parenteral: IV, IM, SC.
    • IV: 100% bioavailability; immediate effect.
    • IM/SC: Depot possible; variable absorption.
  • Inhalational: Rapid onset (anaesthetics, bronchodilators); large SA.
  • Transdermal: Sustained delivery, bypasses first-pass (Fentanyl patch).
• Bioavailability (F): Fraction of drug reaching systemic circulation unchanged.
  • $F = (\frac{AUC_{oral}}{AUC_{IV}}) \times 100%$ (for same dose).
  • IV route: $F = \textbf{100}%$.
  • ↓F due to: First-pass metabolism, poor absorption, instability, formulation.
• First-Pass Metabolism: Pre-systemic metabolism (liver, gut wall) ↓F.
  • Affects: Propranolol, Lignocaine, Nitroglycerin (oral).
  • 📌 "LMNOP": Lignocaine, Morphine, Nitroglycerin, Oestrogens, Propranolol (high first-pass).

⭐ Drugs with high first-pass metabolism (e.g., Lignocaine) require significantly higher oral doses than IV doses to achieve comparable therapeutic effects due to extensive pre-systemic elimination.

Drug Distribution - Spreading Out!

• Drug movement: Blood → Tissues.
• Key Factors:
  • Lipid Solubility: ↑ solubility → ↑ distribution.
  • Ionization (pH-pKa): Non-ionized form crosses membranes.
  • Plasma Protein Binding (PPB):
    • Albumin (acidic drugs: warfarin), α1-acid glycoprotein (basic drugs: lidocaine).
    • Only unbound drug is active & distributes. High PPB → ↓ $V_d$, longer $t_{1/2}$.
  • Blood Flow/Perfusion: Brain, liver, kidney (rapid); Fat, bone (slow).
  • Tissue Affinity: E.g., Iodine (thyroid), Digoxin (heart), Chloroquine (liver, retina).
• Volume of Distribution ($V_d$):
  • Apparent volume drug occupies if concentration throughout body equals plasma concentration.
  • Formula: $V_d = \frac{\text{Total amount of drug in body (Dose)}}{\text{Plasma drug concentration } (C_0)}$
  • Low $V_d$ (< 5L): Confined to plasma (e.g., Heparin).
  • Intermediate $V_d$ (15-20L): ECF (e.g., Aminoglycosides).
  • High $V_d$ (> 40L): Accumulates in tissues (e.g., Chloroquine, Digoxin).
  • Clinical use: Calculate Loading Dose ($LD = V_d \times C_{target}$).
• Redistribution: Highly lipid-soluble IV drugs (e.g., Thiopental) initially to brain, then to muscle/fat → rapid termination of CNS effect.
• Special Barriers:
  • Blood-Brain Barrier (BBB): Tight junctions; P-glycoprotein efflux. Restricts polar drugs. Lipid-soluble drugs pass.
  • Placental Barrier: Most drugs cross to some extent, especially lipid-soluble.

⭐ Drugs with a very high $V_d$ (e.g., Chloroquine, Amiodarone) are not effectively removed by hemodialysis because they are extensively sequestered in tissues, away from the blood being dialyzed.

High‑Yield Points - ⚡ Biggest Takeaways

• Lipid solubility (↑) & low ionization favor drug absorption.
• First-pass metabolism (liver/gut) ↓ oral bioavailability.
• Bioavailability (F) = fraction of drug reaching systemic circulation unchanged.
• Volume of distribution (Vd) reflects tissue drug distribution; high Vd = more in tissues.
• Plasma protein binding: acidic drugs to albumin, basic drugs to α1-acid glycoprotein.
• Only unbound drug is active, distributed, metabolized, excreted.
• P-glycoprotein (MDR1): efflux pump, ↓ absorption, limits brain/placental entry_